Project Summary While the Eastern and Southern African region is home to 6.2% of the world's population, more than half the world's HIV infected people live here. The biggest epidemic is in South Africa, with 7.2 million people living with HIV. Although the rate of new infections has decreased dramatically worldwide from the peak in 1996, one third (270,000) of new infections in Sub-Saharan Africa last year occurred in South Africa. Young adults are disproportionately affected, with 37% of new infections in South Africa occurring in young women between the ages of 15 and 24. Youth are similarly more likely to be infected in the United States. Adolescence represents a critical period of brain maturation, with ongoing myelination, cortical growth and synaptic pruning. Gradual and differential maturation of the limbic system and prefrontal cortex modulates reward and affective behavior, and executive control. HIV infection and ART present further challenges to neurodevelopment and resilience in this vulnerable stage of development. Cognitive impairment in HIV infected children has been demonstrated in several domains, including memory, attention, and general intellectual functioning. There is an urgent need for research on the longitudinal trajectory of neurodevelopment in perinatally-acquired HIV infected (PHIV+) children and adolescents, especially in resource-limited countries. In this study, we will extend our longitudinal follow-up of two extremely well-characterized PHIV+ cohorts, adding neuroimaging and cognitive assessments at 14 and 16 years, and continuing 6-monthly clinical visits. The study will include 80 PHIV+ children from the ?Children with HIV early antiretroviral therapy? (CHER) trial, originally supported by the Comprehensive International Program for Research on AIDS in South Africa (CIPRA-SA). Controls were recruited by a CIPRA-SA supported interlinking vaccine trial. This cohort has been followed clinically since birth, and with cognitive assessments and neuroimaging from the age of 5. The cohort incorporates children who commenced ART before 12 weeks, and children whose treatment was delayed until immunological criteria were met. We will also include 30 PHIV+ children from the IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials Network) P1060 and P1104S studies who started ART at 2 to 36 months after exhibiting relatively advanced disease, and uninfected controls from the same cohort. The Cape Universities Body Imaging Centre (CUBIC) houses a state-of-the-art research-dedicated Siemens 3 T Skyra MRI scanner optimized for brain imaging, and unique in sub-Saharan Africa. We have developed the capability for advanced brain morphometry, spectroscopy, diffusion tensor and functional imaging. This project builds on a successful decade-long collaboration between Dr. Ernesta Meintjes (University of Cape Town), Dr. Barbara Laughton (Stellenbosch University) and Dr. Andr van der Kouwe (Massachusetts General Hospital). The project will build capacity including analysis methods for dynamic functional imaging and advanced spectroscopic imaging techniques.